Complete prevention of postischemic spinal cord injury by means of regional infusion with hypothermic saline and adenosine.

Spinal cord injury after operations on the descending thoracic and thoracoabdominal aorta remains a persistent clinical problem. Previous attempts to decrease the risk of this devastating complication by lowering the rate of metabolism of the spinal cord have met with varying success. We hypothesized that the tolerance of the spinal cord to an ischemic insult could be improved by means of adenosine. Twenty New Zealand white rabbits underwent 40 minutes of isolated infrarenal aortic occlusion after heparin anticoagulation. Clamps were placed both below the left renal vein and above the aortic bifurcation. In 10 rabbits (group A), a bolus of adenosine (100 mg) was infused into the isolated aortic segment immediately after crossclamping and this bolus was followed by a flush of hypothermic saline (8 degrees C, 30 ml/kg) over the first 10 minutes of ischemia. In one control group of five animals (group B), the descending infrarenal aorta was crossclamped without infusion of adenosine or saline. In another control group of five animals (group C), the aortic segment was flushed with normothermic saline (37 degrees C) in a fashion identical to that of the study group. The aortic clamps were removed after 40 minutes, the abdomen was closed, and the animals were allowed to recover from anesthesia. Spinal cord function was assessed 12, 24, 48, 72, and 96 hours after operation by the Tarlov scale. All animals were put to death at 96 hours after operation and spinal cords were harvested for histologic analysis. The spinal cord function of all group A animals was fully intact with Tarlov scores of 5; group B and group C animals were all paraplegic with Tarlov scores of 0 (p < 0.001, general linear models analysis of variance). Histologic examination of spinal cords from group A rabbits revealed no evidence of cord injury, whereas spinal cords from groups B and C had evidence of extensive cord injury with central gray necrosis, axonal swelling, dissolution of Nissl substance, and astrocyte and macrophage infiltration. Regional infusion of the crossclamped infrarenal rabbit aorta with hypothermic saline and adenosine completely prevented paraplegia in our model despite a 40-minute ischemic insult.

Safe ex vivo coronary angiography with isosmotic contrast agent.

Plain-film coronary angiography of the cardiac explant on the operating table should be considered when conventional cardiac catheterization is desired but unavailable. We compared the effects of three contrast solutions on cold-preserved, isolated guinea pig hearts. Hearts were excised, perfused for 30 minutes, and arrested with Plegisol solution at 7 degree C. Twenty minutes after arrest, experimental hearts were perfused with one of three solutions: hyperosmolar Hexabrix solution (n = 6), hyperosmolar Renografin-76 solution (n = 6), or diluted, isosmotic Omnipaque solution (n = 8). The hearts were flushed with cold Plegisol solution 5 minutes later. Control hearts received no contrast during arrest (n = 9). The hearts were reperfused after 1 hour of arrest, and coronary blood flow (in millimeters per minute), left ventricular developed pressure (in millimeters of mercury), and rate of developed pressure (in millimeters of mercury per second) were measured. Endothelium-dependent smooth muscle relaxation to bradykinin administration and endothelium-independent relaxation to sodium nitroprusside administration were also assessed. No significant difference in myocardial or endothelial function was noted between control hearts and hearts perfused with Omnipaque solution. Hearts perfused with Renografin solution or Hexabrix solution, however, were found to have significantly impaired endothelial and myocardial function. We conclude that an isosmotic contrast solution should be used for ex vivo coronary angiography in cold-preserved hearts to avoid impairment of endothelial and myocardial function.

Hypothermic retrograde venous perfusion with adenosine cools the spinal cord and reduces the risk of paraplegia after thoracic aortic clamping.

OBJECTIVE: We evaluated the utility of retrograde venous perfusion to cool the spinal cord and protect neurologic function during aortic clamping. We hypothesized that hypothermic adenosine would preserve the spinal cord during ischemia. METHODS: Six swine (group I) underwent thoracic aortic occlusion for 30 minutes at normothermia. Group II animals underwent spinal cooling by retrograde perfusion of the paravertebral veins with hypothermic (4 degrees C) saline solution during aortic occlusion. The spinal cords of group III animals were cooled with a hypothermic adenosine solution in a similar fashion. Intrathecal temperature was monitored and somatosensory evoked potentials assessed the functional status of spinal pathways. RESULTS: Spinal cooling without systemic hypothermia significantly improved neurologic Tarlov scores in group III (4.8 +/- 0.2) and group II (3.8 +/- 0.4) when compared with group I scores (1.3 +/- 0.6) (P <.001). Furthermore, 5 of the 6 animals in group III displayed completely normal neurologic function, whereas only one animal in group II and no animals in group I did (P =.005). Somatosensory evoked potentials were lost 10.6 +/- 1.4 minutes after ischemia in group I. In contrast, spinal cooling caused rapid cessation of neural transmission with loss of somatosensory evoked potentials at 6.9 +/- 1.2 minutes in group II and 7.0 +/- 0.8 minutes in group III (P =.06). Somatosensory evoked potential amplitudes returned to 85% of baseline in group III and 90% of baseline in group II compared with only 10% of baseline in group I (P =.01). CONCLUSIONS: We conclude that retrograde cooling of the spinal cord is possible and protects against ischemic injury and that adenosine enhances this effect. The efficacy of this method may be at least partly attributed to a more rapid reduction in metabolic and electrical activity of the spinal cord during ischemia.

Growth potential of porcine reduced-size mature pulmonary lobar transplants.

The use of mature pulmonary lobes for pediatric lung transplantation has recently been described. Successful application of this technique could help alleviate the pediatric donor lung shortage. Whether an already mature lobe can grow by forming new alveolar units after transplantation into a developing recipient is not known. We therefore measured functional residual capacity, fixed lung volume and weight, alveolar size and air space volume percent, and total number of alveoli in mature left lower lobe porcine lung transplants 12 weeks after transplantation into growing piglets. Comparisons were made with nontransplanted mature left lower lobes to determine if functional or morphologic growth had occurred after transplantation. The transplanted and control lobes were all taken from 6-month-old animals (mean body weight 105 +/- 4 kg). Recipients of the transplanted lobes were 9 weeks old and weighed 22 +/- 2 kg. By the end of the 12-week holding period, the recipient animals increased their body weight approximately fourfold (85 +/- 4 kg). No significant differences were seen in functional residual capacity or morphologic analysis of total alveolar number and alveolar size between the transplanted and nontransplanted lobes (p = not significant). Although the reduced-size mature porcine lobar transplants did not display a significant increase in either functional residual capacity or total alveolar number, there was significant growth of the transplanted mature lobes as determined by fixed volume and total lobar weight (p < or = 0.05 versus control animals).

Lung transplant reperfusion injury involves pulmonary macrophages and circulating leukocytes in a biphasic response.

OBJECTIVE: Both donor pulmonary macrophages and recipient circulating leukocytes may be involved in reperfusion injury after lung transplantation. By using the macrophage inhibitor gadolinium chloride and leukocyte filters, we attempted to identify the roles of these two populations of cells in lung transplant reperfusion injury. METHODS: With our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest followed by 18-hour cold storage and 2-hour blood reperfusion. Measurements of pulmonary artery pressure, lung compliance, and arterial oxygenation were obtained. Group I (n = 8) served as a control. Group II (n = 8) received gadolinium chloride at 14 mg/kg 24 hours before lung harvest. Group III (n = 8) received leukocyte-depleted blood reperfusion by means of a leukocyte filter. RESULTS: The gadolinium chloride group had significantly improved arterial oxygenation and pulmonary artery pressure measurements compared with control subjects and an improved arterial oxygenation compared with the filter group after 30 minutes of reperfusion. After 120 minutes of reperfusion, however, the filter group had significantly improved arterial oxygenation and pulmonary artery pressure measurements compared with the control group and an improved arterial oxygenation compared with the gadolinium chloride group. CONCLUSIONS: Lung transplant reperfusion injury occurs in two phases. The early phase is mediated by donor pulmonary macrophages and is followed by a late injury induced by recipient circulating leukocytes.

Euro-Collins solution exacerbates lung injury in the setting of high-flow reperfusion.

Single-lung transplantation has been abandoned for the treatment of pulmonary hypertension by many centers because of overperfusion of the graft following implantation. Euro-Collins solution is currently used for lung preservation despite the vasoconstrictive effect of this intracellular-type solution. We hypothesized that high-flow reperfusion, alone or in combination with Euro-Collins-induced vasoconstriction, may cause lung dysfunction. Twenty-eight New Zealand White rabbit lungs were harvested and studied in an isolated, blood-perfused model of lung function after 4 hours of cold ischemia. Control lungs were preserved with 50 ml/kg cold saline solution flush and reperfused at either normal flow (60 ml/min) or high flow (120 ml/min). Experimental lungs were preserved with 50 ml/kg cold Euro-Collins solution and reperfused at normal or high flow rates. The arteriovenous oxygen gradient at the end of the 30-minute reperfusion period was significantly lower in the high-flow versus the low-flow experimental group (31.1 +/- 4.2 vs 130.6 +/- 41.6 mm Hg, p < 0.05). The pulmonary vascular resistance was increased in the high-flow groups and the experimental groups, with a statistically significant difference between low-flow experimental and control groups (64374.4 +/- 5722.6 vs 37041.5 +/- 2110.9 dynes x sec x cm(-5), p < 0.001). The percentage decrease in dynamic airway compliance in the high-flow experimental group was markedly different from that in the high-flow control group (-51% +/- 13.3% vs -10.15% +/- 3.4%, p < 0.05). Similarly, the wet/dry ratio of the lungs in the high-flow experimental group (13.92 +/- 2.32) was significantly greater than that in the low-flow experimental group (6.27 +/- 0.19, p < 0.01) and than that in the high-flow control group (5.88 +/- 0.23, p < 0.001). These data demonstrate that high-flow reperfusion and preservation with Euro-Collins solution are deleterious to lung function, both individually and in combination, in an ex vivo rabbit lung model. Lung preservation with Euro-Collins solution may not be optimal when high-flow reperfusion is anticipated, as in the setting of unilateral lung transplantation for pulmonary hypertension.

Preservation of intercostal arteries during thoracoabdominal aortic aneurysm surgery: a retrospective study.

OBJECTIVE: The purpose of this article was to examine the influence of reimplantation of patent intercostal and lumbar arteries on the incidence of postoperative paraplegia/paraparesis in patients undergoing clamp-and-sew surgical repair of thoracoabdominal aortic aneurysms. METHODS: Data from January 1987 through December 1997 were retrospectively collected on 132 patients. Ninety-one patients in group I underwent aneurysm repairs before January 1995 and did not undergo intercostal artery reimplantation. Group II included the more recent 41 patients who had vessels between the eighth thoracic intercostal and the second lumbar arteries reimplanted to the graft or preserved at the aortic anastomoses. RESULTS: The operative mortality rate was 13.2% (12/91) in group I and 4.9% (2/41) in group II (P =.22). The incidence of postoperative paraplegia was significantly lower in the more recent cohort of patients (8.8% [8/91] in group I vs 0% [0/41] in group II, P =.05). The overall rate of spinal cord dysfunction was lowered from 9.9% (9/91) in group I to 2.4% (1/41) in group II (P =.17). However, a multivariable logistic regression analysis identified only aneurysm extent (Crawford type I and type II) as a predictor of less postoperative spinal cord injury (P =.08). The average aortic crossclamp time in group I was 30.3 +/- 11.5 (SD) minutes, and the time of aortic occlusion in group II was not significantly prolonged, with an average crossclamp time of 31.0 +/- 21.0 (SD) minutes (P =. 88). CONCLUSIONS: An aggressive approach to maintain intercostal artery patency during clamp-and-sew repair of thoracoabdominal aortic aneurysms may effectively lower the incidence of spinal cord injury without prolonging aortic crossclamp time.

Epidermal growth factor augments postpneumonectomy lung growth.

OBJECTIVE: Epidermal growth factor has been shown to play an important role in prenatal and postnatal lung development, but little is known about its effects on adult lung growth. We hypothesized that postpneumonectomy compensatory lung growth can be augmented by the administration of epidermal growth factor. METHODS: Adult Sprague-Dawley rats were divided into 3 groups. Sham left thoracotomy was performed in the first group (group C), left pneumonectomy in the second group (group P), and left pneumonectomy with administration of epidermal growth factor (0.2 microgram/g body weight intraperitoneally, at 72-hour intervals) in the third group (group E). The right lung growth was studied in each group 1, 3, 5, 10, and 21 days after the operation. Lung weights (in grams) and volumes (in milliliters) were expressed as a ratio to the total body weight (in kilograms) (lung weight and volume indices). Epidermal growth factor receptor was quantitated by using Western blotting. RESULTS: Using analysis of variance and contrast analysis, we noted a significant increase in lung weight index in group E versus group P rats at 3 days (3.08 vs 2.75; P =.034) and 21 days (4.62 vs 3.61; P =.006). Lung volume index was significantly increased in group E versus group P rats at 5 (16.98 vs 15.09), 10 (24.48 vs 18.81), and 21 (28.54 vs 21.01) days (P <.001). Epidermal growth factor receptor was noted to be up-regulated in the lungs of animals that received exogenous epidermal growth factor. CONCLUSIONS: This study demonstrates that administration of exogenous epidermal growth factor has a significant effect on postpneumonectomy lung growth. This process may be mediated by an up-regulation of growth factor receptor expression in the contralateral lung.

Both blood and crystalloid-based extracellular solutions are superior to intracellular solutions for lung preservation.

OBJECTIVE: Lung transplantation remains limited by donor organ ischemic time, inadequate graft preservation, and reperfusion injury. We evaluated lung preservation with use of an extracellular solution, with or without the addition of blood, as compared with preservation with the intracellular Euro-Collins solution. METHODS: With use of an isolated, whole blood perfused/ventilated rabbit lung model, we studied three groups of animals. Lungs were flushed with Euro-Collins, low-potassium dextran, or 20% blood-low-potassium dextran solution. Lungs were harvested en bloc, stored inflated at 4 degrees C for 18 hours, and then reperfused at 60 ml/min with whole blood. Continuous measurements of pulmonary artery pressure, pulmonary vascular resistance, and dynamic airway compliance were obtained. Fresh, nonrecirculated venous blood was used to determine the single-pass pulmonary venous-arterial oxygen gradient. RESULTS: Lungs preserved with Euro-Collins solution demonstrated elevated pulmonary artery pressure and pulmonary vascular resistance when compared with those preserved with low-potassium dextran and 20% blood-low-potassium dextran solutions (pulmonary artery pressure: 40.8 +/- 2.2 mm Hg vs 28.9 +/- 2.4 mm Hg and 28.3 +/- 1.5 mm Hg, respectively, p < 0.001; pulmonary vascular resistance: 46.0 +/- 3.1 x 10(3) dynes x sec x cm(-5) vs 29.0 +/- 4.2 x 10(3) dynes x sec x cm(-5) and 28.8 +/- 2.3 x 10(3) dynes x sec x cm(-5), respectively, p < 0.001). Euro-Collins solution-preserved lungs demonstrated a significant drop in compliance when compared with those preserved with low-potassium dextran and 20% blood-low-potassium dextran (-21.9% +/- 4.7% vs 1.8% +/- 3.3% and 1.4% +/- 6.2%, respectively; p = 0.002). Oxygenation was improved with low-potassium dextran and 20% blood-low-potassium dextran solutions as compared with that with Euro-Collins solution (296.3 +/- 54.6 mm Hg and 290.2 +/- 66.4 mm Hg, respectively, vs 37.2 +/- 4.6 mm Hg; p = 0.001). CONCLUSIONS: Extracellular solutions provided superior preservation of pulmonary function in this rabbit lung model of ischemia-reperfusion. However, the addition of blood does not confer any demonstrable advantage over low-potassium dextran solution alone with use of an 18-hour period of cold ischemia.

Mature pulmonary lobar transplants grow in an immature environment.

OBJECTIVE: Mature lobar transplantation will increase the pediatric donor organ pool, but it remains unknown whether such grafts will grow in a developing recipient and provide adequate long-term support. We hypothesized that a mature pulmonary lobar allograft implanted in an immature recipient would grow. METHODS: We investigated our hypothesis in a porcine orthotopic left lung transplant model using animals matched by the major histocompatibility complex to minimize the effects of chronic rejection. Twenty-three immature animals (< 12 weeks of age and < 10 kg total body weight) received either sham left thoracotomy (SH control, n = 4), left upper lobectomy to study compensatory growth (UL control, n = 4), age-matched immature whole left lung transplants (IWL TXP, n = 6), mature (donor > 1 yr in age and > 40 kg in total body weight) left lower lobe transplants (MLL TXP, n = 5), or mature left upper lobe transplants (MUL TXP, n = 4). Twelve weeks after implantation, functional residual capacity of the left lung was measured and arterial blood gas samples were obtained after the native right lung had been excluded. The graft was excised and weighed, and samples for microscopy and wet/dry ratios were collected. RESULTS: Initial and final graft weights were as follows: IWL TXP group (34.6 +/- 1.5 and 107.8 +/- 5.9 gm, p < 0.0001), MLL TXP group (72.4 +/- 6.8 and 111.4 +/- 8.7, p < 0.001), and MUL TXP group (32.8 +/- 1.3 and 92.8 +/- 7.1 gm, respectively, p < 0.004). No significant differences between groups were demonstrated when functional residual capacity, wet/dry ratios, or oxygenation were compared. Immunohistochemical staining for the nuclear antigen Ki-67 demonstrated dividing pneumocytes. CONCLUSIONS: We conclude that a mature lobar graft implanted into an immature recipient grows by pneumocyte division in this model. Mature lobar transplants can be expected to grow and provide adequate long-term function in developing recipients.

Enhanced isolated lung function after ischemia with anti-intercellular adhesion molecule antibody.

The binding of leukocytes to intercellular adhesion molecules expressed on endothelial surfaces during ischemia and subsequent reperfusion initiates leukocyte-mediated reperfusion injury. Interruption of this leukocyte-endothelium interaction may therefore prevent reperfusion injury. In an isolated, ventilated, blood-perfused rabbit lung preparation, we studied the effect of a monoclonal anti-intercellular adhesion molecule antibody on lung function during reperfusion. Lungs were harvested with 50 ml/kg cold Euro-Collins flush and 30 micrograms prostaglandin E1 before storage for 18 hours at 4 degrees C. Experimental groups received low-dose (100 micrograms) or high-dose (200 micrograms) anti-intercellular adhesion molecule antibody added to the pulmonary flush at harvest and to the initial reperfusate. Eighteen-hour control preparations were preserved for 18 hours and received saline solution vehicle. Immediate control preparations were harvested and immediately reperfused. The oxygen tension in the recirculated pulmonary venous effluent was measured after 30 minutes of reperfusion. Histologic specimens were graded by blinded observers for degree of leukocyte infiltration (0, normal, to 4, severe infiltration). The mean oxygen tensions (+/-standard error of the mean) were 138.29 +/- 6.23, 58.86 +/- 9.14, 86.87 +/- 11.32, and 139.33 +/- 16.15 mm Hg in immediate control preparations, 18-hour control preparations, low-dose antibody group, and high-dose antibody group, respectively (p = 0.0001). The leukocyte grades (mean +/- standard error of the mean) were 1.5 +/- 0.723, 3.0 +/- 0.955, 1.9 +/- 0.899, and 1.2 +/- 0.834, respectively (p = 0.0002). We conclude that anti-intercellular adhesion molecule antibody added to the pulmonary flush and initial reperfusate results in a dose-dependent enhancement of the reperfused lung's ability to oxygenate blood, possibly as a result of decreased leukocyte sequestration.

Neutrophil endopeptidase inhibitor improves pulmonary function during reperfusion after eighteen-hour preservation.

BACKGROUND: Reperfusion injury remains a significant problem after lung transplantation and is thought to be in part mediated by neutrophils. Ulinastatin inhibits release of elastase and cathepsin G from neutrophil granules. We hypothesized that inhibition of these neutrophi endopeptidases (proteases) would attenuate pulmonary reperfusion injury. METHODS: With an isolated, whole blood-perfused, ventilated rabbit lung model, we studied the effects of ulinastatin. All lungs were flushed with cold Euro-Collins solution, harvested en bloc, stored inflated at 4 degrees C for 18 hours, and reperfused with whole blood. The 18-hour control lungs (n = 8) were stored and reperfused. Low-dose (n = 8) and high-dose (n = 7) groups were treated with total doses of ulinastatin of 25,000 and 50,000 units, respectively, during flush and reperfusion. An additional control group of lungs (n = 8) was harvested, flushed, and immediately reperfused. RESULTS: The pulmonary artery pressure was significantly lower in the high-dose group than in the 18-hour control group (36.7 +/- 1.8 vs 44.8 +/- 2.9 mm Hg, p = 0.034). The percentage decrease in dynamic airway compliance was significantly less in the high-dose group than in the 18-hour control group (-13.8% +/- 4.4% vs -25.1% +/- 3.7%, p = 0.032). Both low-dose and high-dose ulinastatin treatments did not result in a significant improvement in oxygenation with respect to the 18-hour control group (72.2 +/- 25.8 vs 32.5 +/- 4.9 mm Hg, p = 0.21). CONCLUSIONS: Ulinastatin diminishes reperfusion injury after 18 hours of hypothermic pulmonary ischemia, with resultant improvements in pulmonary artery pressure and airway compliance. Improvement in pulmonary function after preservation and reperfusion with a neutrophil endopeptidase inhibitor confirms the role of endopeptidases in reperfusion injury and suggests an intervention to reduce their detrimental effects on early graft function.

Early intervention after severe oxygenation index elevation improves survival following lung transplantation.

BACKGROUND: Reperfusion injury and technical problems following lung transplantation may result in life-threatening pulmonary dysfunction that requires intervention with either extracorporeal membrane oxygenation or reoperation. Early intervention in these patients could prevent complications associated with delayed or emergent intervention and may improve survival. The oxygenation index [(mean airway pressure x percent of inspired oxygen)/partial pressure of arterial oxygen] provides a rapid assessment of pulmonary function in the critical phase of reperfusion. Our hypothesis was that the oxygenation index could be used as an early predictor for severe respiratory failure requiring acute intervention. METHODS: Analysis of 136 consecutive lung transplant operations revealed 18 patients (reperfusion injury in 16 and technical complications in 2) with an oxygen index of > or = 30. Of those patients with reperfusion injury, 9 had fibrotic lung disease, 4 had obstructive lung disease, and 3 had primary pulmonary hypertension. RESULTS: Patients undergoing transplantation for fibrotic lung diseases were more likely to develop severe reperfusion injury (oxygenation index > or = 30) compared to patients with obstructive lung diseases (9 of 42 or 21% vs 4 or 80 or 5%, p = 0.005). The 5 patients with early intervention (< or = 2 hours) after an oxygenation index elevation above 30 had significantly improved survival compared to the 13 with no or late intervention (80% vs 15% survival, p = 0.02). CONCLUSION: Oxygenation index elevation > or = 30 following lung transplantation is an early predictor of severe respiratory failure requiring acute intervention. Early intervention in these patients improves survival.

Denervation of the immature porcine lung impairs normal airway development.

Reimplantation or allotransplantation of the immature porcine left lower lobe results in long-term functional dynamic airway obstruction that is associated with abnormally small distal airways. We have attributed this small airway size to bronchoconstriction resulting from chronic denervation rather than to impaired airway growth. To further investigate these findings, we transplanted mature left lower lobes from adult pigs into young piglets after left pneumonectomy. After approximately 12 weeks of somatic growth, the lobes were harvested and fixed through the airways with formalin. Cross-sectional areas of terminal, noncartilaginous airways from the lung periphery were traced on a video monitor. Five groups were examined: control innervated mature left lower lobes, innervated left lower lobes subjected to compensatory growth after left upper lobectomy at approximately 9 weeks of age, mature left lower lobe transplants, reimplanted immature left lower lobe autografts, and transplanted immature left lower lobe allografts. Unlike the immature porcine lobe, transplantation of the mature porcine lobe does not result in abnormally small airways. The small airways seen after transplantation or reimplantation of the immature porcine lobe are likely, therefore, to be due to impaired airway development and not to bronchoconstriction caused by denervation.

Selective adenosine-A2A activation reduces lung reperfusion injury following transplantation.

BACKGROUND: The adenosine-A2A receptor on the neutrophil is responsible for several anti-inflammatory actions. We hypothesized that DWH-146e, a selective adenosine-A2A agonist, would reduce lung reperfusion injury following transplantation. METHODS: We used an isolated, whole blood-perfused, ventilated rabbit lung model. Donor rabbits underwent lung harvest after pulmonary arterial PGE1 injection and Euro-Collins preservation solution flush, and lungs were preserved for 18 hours at 4 degrees C. Group I lungs (n = 9) served as control subjects. Group II lungs (n = 9) were reperfused with whole blood that was first passed through a leukocyte-depleting filter. In group III (n = 9), DWH-146e was added to the blood reperfusate (25 microg/kg) immediately before reperfusion and was administered throughout the reperfusion period (1 microg/kg/min). All lungs were reperfused for 30 minutes. RESULTS: Arterial oxygenation in group II and group III was significantly higher than that of group I after 30 minutes of reperfusion (514.27 +/- 35.80 and 461.12 +/- 43.77 vs 91.41 +/- 20.58 mm Hg, p < .001). Pulmonary vascular resistance was significantly reduced in group III (22,783 +/- 357 dynes x s x cm(-5)) compared to both group II and group I (31,057 +/- 1743 and 36,911 +/- 2173 dynes x s x cm(-5), p < .001). Airway compliance was improved in groups II and III when compared to group I (1.68 +/- 0.08 and 1.68 +/- 0.05 vs 1.36 +/- 0.13, p = .03). Microvascular permeability in group III was reduced to 106.82 +/- 17.09 compared with 165.70 +/- 21.83 ng Evans blue dye per gram of tissue in group I (p = .05). Group III myeloperoxidase activity was 39.88 +/- 4.87 compared with 88.70 +/- 18.69 deltaOD/g/min in group I (p = .03); group II myeloperoxidase activity was 56.06 +/- 7.46. CONCLUSIONS: DWH-146e reduced lung neutrophil sequestration and dramatically improved pulmonary graft function. Neutrophils are important components of the inflammatory cascade of reperfusion injury and their source may include both the circulating blood and the lung graft itself. Selective adenosine-A2A activation interrupts the neutrophil-mediated inflammatory response and reduces lung reperfusion injury following transplantation.

Influence of graft ischemic time on outcomes following lung transplantation.

BACKGROUND: Reperfusion injury is the most common cause of early mortality following lung transplantation. Although cold graft ischemic time has been reported to influence this injury, some lung grafts with short ischemic times develop significant reperfusion injury, whereas other grafts with more prolonged ischemic times do not develop injury. Our hypothesis was that ischemic time did not significantly influence reperfusion injury or other outcomes following lung transplantation. METHODS: Data on 136 patients who had lung transplantation over a 10 year period was used for analysis. RESULTS: Cold graft ischemic time > or = 6 hours did not increase the risk of reperfusion injury, acute rejection, cytomegalovirus infection, bacterial or fungal pneumonia, bronchiolitis obliterans syndrome, 1-month mortality, 1-year mortality, or 5-year mortality compared with ischemic times of either < 4 hours or 4 to 6 hours. The incidence of reperfusion injury was at least 20% for each time group. CONCLUSIONS: At least 20% of all patients will develop reperfusion injury regardless of cold graft ischemic time. Prolonged ischemic times up to 8 hours do not result in a significant increase in adverse short-term, intermediate, or long-term outcomes. Cautious extension of ischemic time beyond the current target of 4 to 6 hours may be warranted for geographic expansion of the donor lung pool.

Impaired bronchial healing after lung donation from non-heart-beating donors.

BACKGROUND: Bronchial viability after lung transplantation remains a concern. Modern preservation methods, surgical technique, and limited cold ischemic periods have decreased the frequency of bronchial complications. However, lungs procured from non-heart-beating donors are subjected to a mandatory period of warm ischemia. We investigated bronchial healing in a porcine survival model of left lung transplantation using organ procurement from non-heart-beating donors after a 60-minute period of warm ischemia. METHODS: Fourteen adult domestic swine underwent left lung transplantation. All lungs were preserved with cold Euro-Collins flush and stored inflated at 4 degrees C. Control lungs (n = 5) were flushed, harvested, and stored for 2 hours before implantation. Experimental lungs (n = 9) were procured from non-heart-beating donors. These lungs were subjected to 60 minutes of warm ischemia before flush and harvest, followed by 2 hours of cold storage before implantation. After 21 days of immunosuppression with prednisone, azathioprine, and cyclosporine, pulmonary function was assessed. Bronchial viability was evaluated with bronchoscopy and, at autopsy, followed by histologic analysis. RESULTS: Implantation time did not differ significantly between the control group and the experimental group (59.6 +/- 2.1 versus 64.4 +/- 2.9 minutes, p = 0.24). Control swine exhibited no evidence of ischemic injury to the donor bronchus. In contrast, six of nine lungs procured from non-heart-beating donors showed evidence of ischemic bronchial injury (p = 0.031 versus control). Findings ranged from hypovascular edematous mucosa to necrosis and sloughing of the mucosa throughout the entire donor bronchial tree. The remaining three non-heart-beating donor lungs exhibited normal lung function and bronchial healing. CONCLUSIONS: We conclude that 60 minutes of warm ischemia for lungs procured from non-heart-beating donors results in impaired bronchial viability with current preservation techniques. Thirty minutes of warm ischemia may be the acceptable limit for lung procurement from non-heart-beating organ donors.

Herpes simplex burn wound infections: epidemiology of a case cluster and responses to acyclovir therapy.

Nosocomial transmission of herpes simplex virus (HSV) has been described in intensive care units. A cluster of three patients with HSV wound infections within a 6-week period prompted temporary closure of a burn unit and suggested nosocomial cross infection. However, restriction endonuclease "fingerprint" analysis of the HSV isolates showed them to be genetically and therefore epidemiologically unrelated. This report describes these cases and the use of intravenous acyclovir in the treatment of HSV burn wound infections.

Intern call schedules and their relationship to sleep, operating room participation, stress, and satisfaction.

BACKGROUND: The ideal resident call schedule remains unknown. This study assessed the impact of different call schedules on intern performance and education. METHODS: A year-long, prospective, observational study of first-year residents in a surgery training program was performed with use of intern sleep/operative logs and questionnaires, and faculty questionnaires. RESULTS: Compared with interns taking call every third or fourth night (and cross-covering a separate service), interns taking call every other night reported the greatest amount of fatigue and stress, the lowest satisfaction, and the fewest operative cases. Errors in patient care were not different between schedules. Multivariate analysis revealed that operative participation was inversely related to frequency of night call and level of fatigue post call, stress was related to fatigue while off call and service census, and overall satisfaction was associated with infrequency of call and operative cases performed. Faculty reported more errors by interns cross-covering other services and less operating room participation by interns taking call every other night. CONCLUSIONS: No single resident schedule optimally balances patient care and resident education and satisfaction. All 3 patterns of call studied are acceptable; specific decisions regarding the allocation of house staff manpower should be flexible and dependent on individual service and educational needs.

Adenosine analogue reduces spinal cord reperfusion injury in a time-dependent fashion.

BACKGROUND: We hypothesized that inflammation during spinal cord reperfusion worsens ischemic injury. ATL-146e, an adenosine A(2A) agonist with known anti-inflammatory properties, was used to test this hypothesis at varied intervals to determine the time course of reperfusion injury. METHODS: Forty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group (n = 14 animals) received 0.06 microg/kg/min systemic ATL-146e over 3 hours, beginning after 30 minutes of ischemic time. A second group (n = 6 animals) received ATL-146e over 1.5 hours. A third group (n = 3 animals) received ATL-146e over 1 hour, and a fourth group (n = 17 animals) received saline solution. All animals were assessed at 48 hours for hind limb motor function (Tarlov scale, 0-5). RESULTS: Animals that received ATL-146e for 3 hours (Tarlov score, 4.3 +/- 0.22; P <.001) or 1.5 hours (Tarlov score, 2.7 +/- 0.6; P <.05) had improved neurologic outcomes compared with rabbits that received saline solution (Tarlov score, 0.6 +/- 0.29). Animals that received ATL-146e for 1 hour (Tarlov score, 0.7 +/- 0.8) were not significantly different from those animals that received saline solution. CONCLUSIONS: Systemic ATL-146e, given during reperfusion, results in time-dependent improvement in spinal cord function after ischemia. This implies that the mechanism of spinal reperfusion injury includes leukocyte-mediated inflammation at a critical post-ischemic time interval.